ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1990, 0066-4804/90/061048-05$02.00/0 Copyright © 1990, American Society for Microbiology
p.
1048-1052
Vol. 34, No. 6
Investigation of Potential Interaction of Ciprofloxacin with Cyclosporine in Bone Marrow Transplant Recipients H. U. KRUGER,* U. SCHULER, B. PROKSCH, M. GOBEL, AND G. EHNINGER
Department of Internal Medicine II, University Hospital Tubingen, Otfried-Muller-Strasse 10, 7400 Tubingen, Federal Republic of Germany Received 19 July 1989/Accepted 26 March 1990
The effect of the 4-quinolone antimicrobial agent ciprofloxacin on the concentration in plasma and the pharmacokinetics of the immunosuppressive agent cyclosporine was studied in 10 bone marrow transplant recipients. There were no statistically or clinically significant changes in cyclosporine trough concentrations or areas under the concentration-time curve following oral doses of 500 mg of ciprofloxacin every 12 h for 4 days. The data suggest a lack of relevant pharmacokinetic interaction of ciprofloxacin with cyclosporine. There was no indication of an enhanced nephrotoxicity for this drug combination.
Ciprofloxacin is a new 4-quinolone antimicrobial agent for parenteral and oral use that is highly active against a broad spectrum of microbial pathogens. It has a high oral bioavailability of 70 to 80% and is eliminated mainly by renal mechanisms but also by the intestine (3, 9). Thus, ciprofloxacin achieves high concentrations in feces and the intestinal mucosa. These characteristics suggest a potential application in decontamination and infection prophylaxis of immunocompromised patients (17). However, ciprofloxacin has also been demonstrated to inhibit hepatic drug metabolism. Pharmacokinetic interactions by this mechanism with theophylline, caffeine, and antipyrine are known (7, 12). The immunosuppressive agent cyclosporine has a variable oral bioavailability, a low therapeutic index, and severe concentration-dependent adverse effects which require therapeutic drug monitoring (4, 15). Many pharmacokinetic interactions of other drugs with cyclosporine have been reported (6, 18), since cyclosporine is metabolized by the hepatic oxidase system (4). We investigated a possible interaction of ciprofloxacin with cyclosporine. MATERIALS AND METHODS Study design. In an open, noncomparative pharmacokinetic study, we evaluated the effect of 500 mg of ciprofloxacin administered orally every 12 h for 4 consecutive days on the concentration in plasma and pharmacokinetics of cyclosporine in 10 bone marrow transplant recipients. All patients received oral maintenance therapy of cyclosporine at a constant dosage twice daily. The cyclosporine doses ranged from 100 to 400 mg (2 to 5 mg/kg of body weight; mean, 223 mg). The study design was approved by the ethics committee of the University of Tubingen. Patient characteristics. Ten bone marrow transplant recipients entered the study (three females and seven males). Their ages ranged from 20 to 50 years, and the median age was 34. Diagnoses were chronic myeloid leukemia in six patients, acute myeloid leukemia in two patients, and acute lymphoblastic leukemia in two patients. The conditioning regimens employed cyclophosphamide and total body irradiation (six patients), cyclophosphamide plus vepesid plus total body irradiation (two patients), or cyclophosphamide and busulfan without irradiation (two patients). The graftversus-host disease (GvHD) prophylaxis was cyclosporine *
Corresponding author.
(six patients) or cyclosporine and methotrexate (four patients). All patients at the time of this study were, after bone marrow transplantation, in a stable phase regarding graft function, GvHD, hepatic and renal functions, and further drug administration that included oral acyclovir, oral amphotericin B, and prednisolone in dosages below 2 mg/kg of body weight. None of the patients took metoclopramide or anticholinergics. Serum creatinine concentrations ranged from 0.6 to 1.3 mg/dl before the study. Patient 2 and patient 6 had normal hepatic parameters before the study. Slight elevations of liver enzymes (serum glutamic oxalacetic transferase [SGOT] and serum glutamic pyruvic transferase [SGPT], 0.05). Nephrotoxicity. The baseline mean value of serum creatinine concentration was 1.00 mg/dl (range, 0.6 to 1.3 mg/dl). At day 4 of ciprofloxacin administration, the mean serum creatinine was 0.99 mg/dl (range, 0.7 to 1.2 mg/dl) and after the study it was 1.02 mg/dl (range, 0.8 to 1.5 mg/dl). Patient 1, with a baseline serum creatinine of 1.3 mg/dl and 1.2 mg/dl during the study period, exhibited a creatinine increase to 1.5 mg/dl 6 days after the end of ciprofloxacin administration without further progression. Hepatic status. Clinically significant changes in liver enzymes during the study period were observed in patients 5 and 9. Both patients had markedly elevated transaminase levels before entering the study. While in patient 9 SGPT levels decreased continuously from 133 to 55 IU/liter and SGOT levels reached normal values, patient 5 showed a
further increase of the already elevated liver enzymes after the study. In this case, a liver GvHD was diagnosed in due course.
Ciprofloxacin concentration. Ciprofloxacin concentrations in serum after dose 1 and at day 4 of administration are shown in Table 3. The peak levels after dose 1 ranged from 417 to 1,989 (mean, 1,385) ng/ml. The peak levels at day 4 of ciprofloxacin administration ranged from 1,012 to 4,127 (mean 1,986) ng/ml. DISCUSSION The overall findings of cyclosporine trough concentrations in plasma and AUCs following ciprofloxacin administration showed no statistically significant differences (P > 0.05) or discernible tendencies for change. Considering the patients separately, patients 1, 2, and 8 exhibited increases of cyclos-
LACK OF INTERACTION OF CIPROFLOXACIN WITH CYCLOSPORINE
VOL. 34, 1990 6000
1051
_ before
5000 day
4000
E
day 4
Ciprofloxacin 3000
0. S £
B b. U
2000
06
1000
l
2
3
5
4
6 patient no.
7
8
9
10
FIG. 2. Cyclosporine AUCs (RIA concentrations) before and at days 1 and 4 of ciprofloxacin administration.
porine AUCs during the study period. The AUC of patient 1 was 2.2-fold higher at day 1 and 2.5-fold higher at day 4 than before the study. Patient 2 had increases over the baseline AUC value of 1.5-fold at day 1 and 1.8-fold at day 4. Patient 8 showed an unchanged AUC at day 1 but a 3.4-fold increase TABLE 3. Ciprofloxacin concentrations in serum measured by high-pressure liquid chromatography after dose 1 (day 1) and at day 4 of administration Patient Day no.
Ciprofloxacin concn (ng/ml) at time (h) after dosing 0.5
0
1
2
3
4
6
8
12
1
1 4
0 164
50 1,714 1,730 1,140 172 728 1,672 1,130
816 904
556 408 154 612 466 224
2
1 4
0 233
826 1,295 935 733 736 1,604 1,683 1,255
528 853
338 185 78 353 232 117
3
1 4
0 1,631 1,766 1,432 1,105 841 349 408 1,564 2,144 1,668 1,429
661 543 230 899 648 362
4
1 4
0 806
5
1 4
0 26 NA- 126
177 115
6
1 4
0 201
104 1,500 110 169
7
1 4
8
1 4
0 68
9
1 4
0 96
10
1 4
1%
333 1,742 1,220 837 688 417 402 167 844 1,329 2,091 2,011 2,029 1,259 912 580
0 124
249 392 393 382 2,017 1,437 864 590 305 1,012
646 599 290 818 486 NA 340 205 76 783 538 233
0 66 1,145 1,648 968 0 4,127 2,581 1,493 1,058
846 897
361 217 51 415 204 58
729 1,120 746 1,047
821 900
249 128 386 214
0
0 98
85 477
52 52
0 1,989 1,322 699 493 239 0 0 2% 1,322 2,308 2,299 1,619 1,009 715 541
0 121
a NA, Value not available.
0 0 243 1,761
233 883
326 769
417 267 111 343 228 106
of the AUC at day 4. Patients 1 and 2 had no remarkable variations of the cyclosporine trough levels; the cyclosporine trough concentration at day 4 was 1.2-fold higher by RIA and 1.4-fold higher by FPIA in patient 8. Another patient with a strongly increased cyclosporine trough level was patient 6, who had a 1.7-fold increase over the baseline level by RIA and a 1.5-fold increase over the baseline level by FPIA at day 4 of ciprofloxacin administration without a concomitant increase of the cyclosporine AUC. Patients on cyclosporine show wide fluctuations in cyclosporine concentration that depend on changes in food intake, concomitant drugs, fluid balance, and any pathophysiological conditions of renal and liver function. Thus, patient 8 already exhibited striking variations of cyclosporine trough levels before starting ciprofloxacin. At day 1, the cyclosporine trough concentration before the first ciprofloxacin dose was decreased to 42 (RIA) and 40% (FPIA) of the trough levels of 24 h before. Since no other alterations appeared concerning concomitant drugs or diseases, these changes must be attributed to the large intraindividual variability in the oral bioavailability of cyclosporine. With regard to this regularly observed variation of cyclosporine concentrations in serum, the changes of cyclosporine trough levels and also AUCs in a few individuals observed in this study seem to be relatively minor. Even if these patients represented a subpopulation which is more susceptible to the effects of ciprofloxacin, a severe pharmacokinetic interaction of ciprofloxacin (500 mg orally every 12 h) with cyclosporine, causing toxic concentrations of cyclosporine within a few days (as is, for example, the case with ketoconazole), can be excluded. We conclude that ciprofloxacin can be used as an antimicrobial agent in cyclosporine-treated patients. In our experience, ciprofloxacin treatment is safe when cyclosporine concentrations in plasma are monitored twice weekly during the first weeks of drug administration. A further intensification of cyclosporine monitoring is not required. Hooper et al. (10) reported three cases of legionella infections in cardiac transplant patients. All of them received ciprofloxacin at higher doses for 2 to 4 weeks and showed no
1052
KROGER ET AL.
alteration of their cyclosporine levels. These data and observations are consistent with our results. Additionally, Tan et al. (16) previously studied potential pharmacokinetic interactions between ciprofloxacin and cyclosporine in healthy volunteers and saw no significant differences in the pharmacokinetic parameters of cyclosporine. The study was done with only a single cyclosporine dose of 5 mg/kg before and on day 7 of an 8-day course of 500 mg of ciprofloxacin orally every 12 h. Because of the ethical considerations involved in giving cyclosporine to volunteers for an extended period, we decided to use a study design with cyclosporine-treated patients and accepted the disadvantages of multiple, concurrent drugs and underlying and concomitant diseases with potential influence on cyclosporine bioavailability. To our knowledge, there has been only one case report suggesting a pharmacokinetic interaction between ciprofloxacin and cyclosporine. Castelao et al. (5) observed an increase of the cyclosporine level in blood from 410 to 1,050 ng/ml in a 15-year-old patient after ciprofloxacin administration. However, no further specific details are given in this report. With respect to our experiences, slight to moderate variations of the cyclosporine levels in such single observations could be caused more often by a change of the largely variable bioavailability. Thus, the probable lack of pharmacokinetic interaction between ciprofloxacin and cyclosporine allows the conclusion that cyclosporine oxidation is carried out by another isoenzyme of cytochrome P-450 rather than by oxidation of theophylline, caffeine, and antipyrine. This isoenzyme is apparently not inhibited by ciprofloxacin. In two case reports, a synergistic nephrotoxicity of the combination of cyclosporine and ciprofloxacin was suspected without evidence of elevation of cyclosporine levels (1, 8). The 10 patients in our study demonstrated only slight changes in serum creatinine, as is usually observed under cyclosporine treatment. Regarding our data, there was no indication of a synergistic nephrotoxicity; however, it must be considered that ciprofloxacin administration lasted only 4 days. Peak ciprofloxacin levels higher than 1.0 mg/liter in all patients and a mean peak concentration of 2.0 mg/liter at day 4 of drug administration demonstrate sufficient oral bioavailability of ciprofloxacin. Nevertheless, peak levels were lower than those reported from healthy volunteers (3, 9). The time to a maximum ciprofloxacin concentration in serum was also prolonged in our patients. The courses of the ciprofloxacin concentration-time curves suggest an interaction in the absorptive phase as the cause for these observations. None of the patients took antacids with ciprofloxacin, which is known to result in a marked decrease of ciprofloxacin absorption (7). However, a reduction of absorption due to other concurrently administered drugs or food intake has to be considered. In healthy volunteers, concurrent food intake causes a retardation of ciprofloxacin absorption but no relevant decrease of absorption rate (11). It must be borne in mind that the patients studied here were bone marrow transplant recipients, and although there was no severe GvHD present at the study time, the intestine could still have been affected by previous conditioning or underlying or concomitant diseases, including slight GvHD of the intestine. This cannot be excluded as contributing to decreased
ANTIMICROB. AGENTS CHEMOTHER.
ciprofloxacin absorption. Nevertheless, this consideration does not materially alter our conclusion of a lack of severe pharmacokinetic interaction between the two drugs. LITERATURE CITED 1. Avent, C. K., D. Krinsky, J. K. Kirklin, R. C. Bourge, and W. D. Figg. 1988. Synergistic nephrotoxicity due to ciprofloxacin and cyclosporine. Am. J. Med. 85:452-453. 2. Awni, W., J. Clarkson, and D. Guay. 1987. Determination of ciprofloxacin and its 7-ethylenediamine metabolite in human serum and urine by high-performance liquid chromatography. J. Chromatogr. 419:414-420. 3. Bergan, T., S. B. Thorsteinsson, R. Solberg, L. Bjornskau, I. M. Kolstad, and S. Johnsen. 1987. Pharmacokinetics of ciprofloxacin: intravenous and increasing oral doses. Am. J. Med. 82(Suppl. 4A):97-102. 4. Beveridge, T. 1982. Pharmacokinetics and metabolism of cyclosporin A, p. 35-44. In D J. White (ed.), Cyclosporin A. Elsevier Biomedical Press, Amsterdam. 5. Castelao, A. M., I. Sabate, J. M. Grino, S. Gil-Vernet, E. Andres, R. Sabater, and J. Alsina. 1988. Cyclosporine-drug interactions. Transplant. Proc. 20(Suppl 6):66-69. 6. Cockburn, I. 1986. Cyclosporine A: a clinical evaluation of drug interactions. Transplant. Proc. 18:50-55. 7. Davey, P. G. 1988. Overview of drug interactions with the quinolones. J. Antimicrob. Chemother. 22(Suppl. C):97-107. 8. Elston, R. A., and J. Taylor. 1988. Possible interaction of ciprofloxacin with cyclosporin A. J. Antimicrob. Chemother. 21:679-680. 9. Gonzalez, M. A., F. Uribe, S. D. Moisen, A. P. Fuster, A. Selen, P. Welling, and B. Painter. 1984. Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob. Agents Chemother. 26:741-744. 10. Hooper, T. L., F. K. Gould, C. R. Swinburn, G. Featherstone, N. J. Odom, P. A. Corris, R. Freeman, and C. G. McGregor. 1988. Ciprofloxacin: a preferred treatment for legionella infections in patients receiving cyclosporin A. J. Antimicrob. Chemother. 22:952-953. 11. Ledergerber, B., J.-D. Bettex, B. Joos, M. Flepp, and R. Luthy. 1985. Effect of standard breakfast on drug absorption and multiple-dose pharmacokinetics of ciprofloxacin. Antimicrob. Agents Chemother. 27:350-352. 12. Ludwig, E., E. Szekely, A. Csiba, and H. Graber. 1988. The effect of ciprofloxacin on antipyrine metabolism. J. Antimicrob. Chemother. 22:61-67. 13. McBride, J. H., D. 0. Rodgerson, S. S. Park, and A. F. Reyes. 1989. Measurement of cyclosporine in plasma from patients with various transplants: HPLC and radioimmunoassay with a specific monoclonal antibody compared. Clin. Chem. 35:17261730. 14. Mraz, W., C. Muller, and M. Knedel. 1988. The analysis of cyclosporin A (CsA) concentrations by fluorescence polarization immunoassay (FPIA). Comparison with radio immunoassay (RIA) and liquid chromatography (HPLC). GIT Labormedizin 11:591-593. 15. Ptachcinski, R., R. Venkataramanan, and G. Burckard. 1986. Clinical pharmacokinetics of cyclosporin. Clin. Pharmacokinet. 11:107-132. 16. Tan, K. K., A. K. Trull, and S. Shawket. 1988. Study of the potential pharmacokinetic interaction between ciprofloxacin and cyclosporin in man. Br. J. Clin. Pharmacol. 26:644-645. 17. Van Saene, H. K., S. E. Lemmens, and J. J. van Saene. 1988. Gut decontamination by oral ofloxacin and ciprofloxacin in healthy volunteers. J. Antimicrob. Chemother. 22(Suppl C):127-134. 18. Wadhwa, N. K., T. J. Schroeder, A. J. Pesce, S. A. Myre, C. W. Clardy, and M. R. First. 1987. Cyclosporine drug interactions: a review. Ther. Drug Monit. 9:399-406.
p.
1048-1052
Vol. 34, No. 6
Investigation of Potential Interaction of Ciprofloxacin with Cyclosporine in Bone Marrow Transplant Recipients H. U. KRUGER,* U. SCHULER, B. PROKSCH, M. GOBEL, AND G. EHNINGER
Department of Internal Medicine II, University Hospital Tubingen, Otfried-Muller-Strasse 10, 7400 Tubingen, Federal Republic of Germany Received 19 July 1989/Accepted 26 March 1990
The effect of the 4-quinolone antimicrobial agent ciprofloxacin on the concentration in plasma and the pharmacokinetics of the immunosuppressive agent cyclosporine was studied in 10 bone marrow transplant recipients. There were no statistically or clinically significant changes in cyclosporine trough concentrations or areas under the concentration-time curve following oral doses of 500 mg of ciprofloxacin every 12 h for 4 days. The data suggest a lack of relevant pharmacokinetic interaction of ciprofloxacin with cyclosporine. There was no indication of an enhanced nephrotoxicity for this drug combination.
Ciprofloxacin is a new 4-quinolone antimicrobial agent for parenteral and oral use that is highly active against a broad spectrum of microbial pathogens. It has a high oral bioavailability of 70 to 80% and is eliminated mainly by renal mechanisms but also by the intestine (3, 9). Thus, ciprofloxacin achieves high concentrations in feces and the intestinal mucosa. These characteristics suggest a potential application in decontamination and infection prophylaxis of immunocompromised patients (17). However, ciprofloxacin has also been demonstrated to inhibit hepatic drug metabolism. Pharmacokinetic interactions by this mechanism with theophylline, caffeine, and antipyrine are known (7, 12). The immunosuppressive agent cyclosporine has a variable oral bioavailability, a low therapeutic index, and severe concentration-dependent adverse effects which require therapeutic drug monitoring (4, 15). Many pharmacokinetic interactions of other drugs with cyclosporine have been reported (6, 18), since cyclosporine is metabolized by the hepatic oxidase system (4). We investigated a possible interaction of ciprofloxacin with cyclosporine. MATERIALS AND METHODS Study design. In an open, noncomparative pharmacokinetic study, we evaluated the effect of 500 mg of ciprofloxacin administered orally every 12 h for 4 consecutive days on the concentration in plasma and pharmacokinetics of cyclosporine in 10 bone marrow transplant recipients. All patients received oral maintenance therapy of cyclosporine at a constant dosage twice daily. The cyclosporine doses ranged from 100 to 400 mg (2 to 5 mg/kg of body weight; mean, 223 mg). The study design was approved by the ethics committee of the University of Tubingen. Patient characteristics. Ten bone marrow transplant recipients entered the study (three females and seven males). Their ages ranged from 20 to 50 years, and the median age was 34. Diagnoses were chronic myeloid leukemia in six patients, acute myeloid leukemia in two patients, and acute lymphoblastic leukemia in two patients. The conditioning regimens employed cyclophosphamide and total body irradiation (six patients), cyclophosphamide plus vepesid plus total body irradiation (two patients), or cyclophosphamide and busulfan without irradiation (two patients). The graftversus-host disease (GvHD) prophylaxis was cyclosporine *
Corresponding author.
(six patients) or cyclosporine and methotrexate (four patients). All patients at the time of this study were, after bone marrow transplantation, in a stable phase regarding graft function, GvHD, hepatic and renal functions, and further drug administration that included oral acyclovir, oral amphotericin B, and prednisolone in dosages below 2 mg/kg of body weight. None of the patients took metoclopramide or anticholinergics. Serum creatinine concentrations ranged from 0.6 to 1.3 mg/dl before the study. Patient 2 and patient 6 had normal hepatic parameters before the study. Slight elevations of liver enzymes (serum glutamic oxalacetic transferase [SGOT] and serum glutamic pyruvic transferase [SGPT], 0.05). Nephrotoxicity. The baseline mean value of serum creatinine concentration was 1.00 mg/dl (range, 0.6 to 1.3 mg/dl). At day 4 of ciprofloxacin administration, the mean serum creatinine was 0.99 mg/dl (range, 0.7 to 1.2 mg/dl) and after the study it was 1.02 mg/dl (range, 0.8 to 1.5 mg/dl). Patient 1, with a baseline serum creatinine of 1.3 mg/dl and 1.2 mg/dl during the study period, exhibited a creatinine increase to 1.5 mg/dl 6 days after the end of ciprofloxacin administration without further progression. Hepatic status. Clinically significant changes in liver enzymes during the study period were observed in patients 5 and 9. Both patients had markedly elevated transaminase levels before entering the study. While in patient 9 SGPT levels decreased continuously from 133 to 55 IU/liter and SGOT levels reached normal values, patient 5 showed a
further increase of the already elevated liver enzymes after the study. In this case, a liver GvHD was diagnosed in due course.
Ciprofloxacin concentration. Ciprofloxacin concentrations in serum after dose 1 and at day 4 of administration are shown in Table 3. The peak levels after dose 1 ranged from 417 to 1,989 (mean, 1,385) ng/ml. The peak levels at day 4 of ciprofloxacin administration ranged from 1,012 to 4,127 (mean 1,986) ng/ml. DISCUSSION The overall findings of cyclosporine trough concentrations in plasma and AUCs following ciprofloxacin administration showed no statistically significant differences (P > 0.05) or discernible tendencies for change. Considering the patients separately, patients 1, 2, and 8 exhibited increases of cyclos-
LACK OF INTERACTION OF CIPROFLOXACIN WITH CYCLOSPORINE
VOL. 34, 1990 6000
1051
_ before
5000 day
4000
E
day 4
Ciprofloxacin 3000
0. S £
B b. U
2000
06
1000
l
2
3
5
4
6 patient no.
7
8
9
10
FIG. 2. Cyclosporine AUCs (RIA concentrations) before and at days 1 and 4 of ciprofloxacin administration.
porine AUCs during the study period. The AUC of patient 1 was 2.2-fold higher at day 1 and 2.5-fold higher at day 4 than before the study. Patient 2 had increases over the baseline AUC value of 1.5-fold at day 1 and 1.8-fold at day 4. Patient 8 showed an unchanged AUC at day 1 but a 3.4-fold increase TABLE 3. Ciprofloxacin concentrations in serum measured by high-pressure liquid chromatography after dose 1 (day 1) and at day 4 of administration Patient Day no.
Ciprofloxacin concn (ng/ml) at time (h) after dosing 0.5
0
1
2
3
4
6
8
12
1
1 4
0 164
50 1,714 1,730 1,140 172 728 1,672 1,130
816 904
556 408 154 612 466 224
2
1 4
0 233
826 1,295 935 733 736 1,604 1,683 1,255
528 853
338 185 78 353 232 117
3
1 4
0 1,631 1,766 1,432 1,105 841 349 408 1,564 2,144 1,668 1,429
661 543 230 899 648 362
4
1 4
0 806
5
1 4
0 26 NA- 126
177 115
6
1 4
0 201
104 1,500 110 169
7
1 4
8
1 4
0 68
9
1 4
0 96
10
1 4
1%
333 1,742 1,220 837 688 417 402 167 844 1,329 2,091 2,011 2,029 1,259 912 580
0 124
249 392 393 382 2,017 1,437 864 590 305 1,012
646 599 290 818 486 NA 340 205 76 783 538 233
0 66 1,145 1,648 968 0 4,127 2,581 1,493 1,058
846 897
361 217 51 415 204 58
729 1,120 746 1,047
821 900
249 128 386 214
0
0 98
85 477
52 52
0 1,989 1,322 699 493 239 0 0 2% 1,322 2,308 2,299 1,619 1,009 715 541
0 121
a NA, Value not available.
0 0 243 1,761
233 883
326 769
417 267 111 343 228 106
of the AUC at day 4. Patients 1 and 2 had no remarkable variations of the cyclosporine trough levels; the cyclosporine trough concentration at day 4 was 1.2-fold higher by RIA and 1.4-fold higher by FPIA in patient 8. Another patient with a strongly increased cyclosporine trough level was patient 6, who had a 1.7-fold increase over the baseline level by RIA and a 1.5-fold increase over the baseline level by FPIA at day 4 of ciprofloxacin administration without a concomitant increase of the cyclosporine AUC. Patients on cyclosporine show wide fluctuations in cyclosporine concentration that depend on changes in food intake, concomitant drugs, fluid balance, and any pathophysiological conditions of renal and liver function. Thus, patient 8 already exhibited striking variations of cyclosporine trough levels before starting ciprofloxacin. At day 1, the cyclosporine trough concentration before the first ciprofloxacin dose was decreased to 42 (RIA) and 40% (FPIA) of the trough levels of 24 h before. Since no other alterations appeared concerning concomitant drugs or diseases, these changes must be attributed to the large intraindividual variability in the oral bioavailability of cyclosporine. With regard to this regularly observed variation of cyclosporine concentrations in serum, the changes of cyclosporine trough levels and also AUCs in a few individuals observed in this study seem to be relatively minor. Even if these patients represented a subpopulation which is more susceptible to the effects of ciprofloxacin, a severe pharmacokinetic interaction of ciprofloxacin (500 mg orally every 12 h) with cyclosporine, causing toxic concentrations of cyclosporine within a few days (as is, for example, the case with ketoconazole), can be excluded. We conclude that ciprofloxacin can be used as an antimicrobial agent in cyclosporine-treated patients. In our experience, ciprofloxacin treatment is safe when cyclosporine concentrations in plasma are monitored twice weekly during the first weeks of drug administration. A further intensification of cyclosporine monitoring is not required. Hooper et al. (10) reported three cases of legionella infections in cardiac transplant patients. All of them received ciprofloxacin at higher doses for 2 to 4 weeks and showed no
1052
KROGER ET AL.
alteration of their cyclosporine levels. These data and observations are consistent with our results. Additionally, Tan et al. (16) previously studied potential pharmacokinetic interactions between ciprofloxacin and cyclosporine in healthy volunteers and saw no significant differences in the pharmacokinetic parameters of cyclosporine. The study was done with only a single cyclosporine dose of 5 mg/kg before and on day 7 of an 8-day course of 500 mg of ciprofloxacin orally every 12 h. Because of the ethical considerations involved in giving cyclosporine to volunteers for an extended period, we decided to use a study design with cyclosporine-treated patients and accepted the disadvantages of multiple, concurrent drugs and underlying and concomitant diseases with potential influence on cyclosporine bioavailability. To our knowledge, there has been only one case report suggesting a pharmacokinetic interaction between ciprofloxacin and cyclosporine. Castelao et al. (5) observed an increase of the cyclosporine level in blood from 410 to 1,050 ng/ml in a 15-year-old patient after ciprofloxacin administration. However, no further specific details are given in this report. With respect to our experiences, slight to moderate variations of the cyclosporine levels in such single observations could be caused more often by a change of the largely variable bioavailability. Thus, the probable lack of pharmacokinetic interaction between ciprofloxacin and cyclosporine allows the conclusion that cyclosporine oxidation is carried out by another isoenzyme of cytochrome P-450 rather than by oxidation of theophylline, caffeine, and antipyrine. This isoenzyme is apparently not inhibited by ciprofloxacin. In two case reports, a synergistic nephrotoxicity of the combination of cyclosporine and ciprofloxacin was suspected without evidence of elevation of cyclosporine levels (1, 8). The 10 patients in our study demonstrated only slight changes in serum creatinine, as is usually observed under cyclosporine treatment. Regarding our data, there was no indication of a synergistic nephrotoxicity; however, it must be considered that ciprofloxacin administration lasted only 4 days. Peak ciprofloxacin levels higher than 1.0 mg/liter in all patients and a mean peak concentration of 2.0 mg/liter at day 4 of drug administration demonstrate sufficient oral bioavailability of ciprofloxacin. Nevertheless, peak levels were lower than those reported from healthy volunteers (3, 9). The time to a maximum ciprofloxacin concentration in serum was also prolonged in our patients. The courses of the ciprofloxacin concentration-time curves suggest an interaction in the absorptive phase as the cause for these observations. None of the patients took antacids with ciprofloxacin, which is known to result in a marked decrease of ciprofloxacin absorption (7). However, a reduction of absorption due to other concurrently administered drugs or food intake has to be considered. In healthy volunteers, concurrent food intake causes a retardation of ciprofloxacin absorption but no relevant decrease of absorption rate (11). It must be borne in mind that the patients studied here were bone marrow transplant recipients, and although there was no severe GvHD present at the study time, the intestine could still have been affected by previous conditioning or underlying or concomitant diseases, including slight GvHD of the intestine. This cannot be excluded as contributing to decreased
ANTIMICROB. AGENTS CHEMOTHER.
ciprofloxacin absorption. Nevertheless, this consideration does not materially alter our conclusion of a lack of severe pharmacokinetic interaction between the two drugs. LITERATURE CITED 1. Avent, C. K., D. Krinsky, J. K. Kirklin, R. C. Bourge, and W. D. Figg. 1988. Synergistic nephrotoxicity due to ciprofloxacin and cyclosporine. Am. J. Med. 85:452-453. 2. Awni, W., J. Clarkson, and D. Guay. 1987. Determination of ciprofloxacin and its 7-ethylenediamine metabolite in human serum and urine by high-performance liquid chromatography. J. Chromatogr. 419:414-420. 3. Bergan, T., S. B. Thorsteinsson, R. Solberg, L. Bjornskau, I. M. Kolstad, and S. Johnsen. 1987. Pharmacokinetics of ciprofloxacin: intravenous and increasing oral doses. Am. J. Med. 82(Suppl. 4A):97-102. 4. Beveridge, T. 1982. Pharmacokinetics and metabolism of cyclosporin A, p. 35-44. In D J. White (ed.), Cyclosporin A. Elsevier Biomedical Press, Amsterdam. 5. Castelao, A. M., I. Sabate, J. M. Grino, S. Gil-Vernet, E. Andres, R. Sabater, and J. Alsina. 1988. Cyclosporine-drug interactions. Transplant. Proc. 20(Suppl 6):66-69. 6. Cockburn, I. 1986. Cyclosporine A: a clinical evaluation of drug interactions. Transplant. Proc. 18:50-55. 7. Davey, P. G. 1988. Overview of drug interactions with the quinolones. J. Antimicrob. Chemother. 22(Suppl. C):97-107. 8. Elston, R. A., and J. Taylor. 1988. Possible interaction of ciprofloxacin with cyclosporin A. J. Antimicrob. Chemother. 21:679-680. 9. Gonzalez, M. A., F. Uribe, S. D. Moisen, A. P. Fuster, A. Selen, P. Welling, and B. Painter. 1984. Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob. Agents Chemother. 26:741-744. 10. Hooper, T. L., F. K. Gould, C. R. Swinburn, G. Featherstone, N. J. Odom, P. A. Corris, R. Freeman, and C. G. McGregor. 1988. Ciprofloxacin: a preferred treatment for legionella infections in patients receiving cyclosporin A. J. Antimicrob. Chemother. 22:952-953. 11. Ledergerber, B., J.-D. Bettex, B. Joos, M. Flepp, and R. Luthy. 1985. Effect of standard breakfast on drug absorption and multiple-dose pharmacokinetics of ciprofloxacin. Antimicrob. Agents Chemother. 27:350-352. 12. Ludwig, E., E. Szekely, A. Csiba, and H. Graber. 1988. The effect of ciprofloxacin on antipyrine metabolism. J. Antimicrob. Chemother. 22:61-67. 13. McBride, J. H., D. 0. Rodgerson, S. S. Park, and A. F. Reyes. 1989. Measurement of cyclosporine in plasma from patients with various transplants: HPLC and radioimmunoassay with a specific monoclonal antibody compared. Clin. Chem. 35:17261730. 14. Mraz, W., C. Muller, and M. Knedel. 1988. The analysis of cyclosporin A (CsA) concentrations by fluorescence polarization immunoassay (FPIA). Comparison with radio immunoassay (RIA) and liquid chromatography (HPLC). GIT Labormedizin 11:591-593. 15. Ptachcinski, R., R. Venkataramanan, and G. Burckard. 1986. Clinical pharmacokinetics of cyclosporin. Clin. Pharmacokinet. 11:107-132. 16. Tan, K. K., A. K. Trull, and S. Shawket. 1988. Study of the potential pharmacokinetic interaction between ciprofloxacin and cyclosporin in man. Br. J. Clin. Pharmacol. 26:644-645. 17. Van Saene, H. K., S. E. Lemmens, and J. J. van Saene. 1988. Gut decontamination by oral ofloxacin and ciprofloxacin in healthy volunteers. J. Antimicrob. Chemother. 22(Suppl C):127-134. 18. Wadhwa, N. K., T. J. Schroeder, A. J. Pesce, S. A. Myre, C. W. Clardy, and M. R. First. 1987. Cyclosporine drug interactions: a review. Ther. Drug Monit. 9:399-406.
